The present invention relates to a new compound which we have named "Thiomarinol" and which has the formula shown hereinbelow. The invention also provides methods of preparing thiomarinol comprising fermentation using a microorganism of the genus Alteromonas, and especially a strain of the new species Alteromonas rava, designated SANK 73390, which is itself new and forms part of the present invention. Thiomarinol has a variety of therapeutic, especially antibacterial, effects, and, thus, the invention also provides compositions and methods of therapy or prophylaxis using this compound.
Organisms of the genus Alteromonas can be isolated from seawater, and some have been shown to produce compounds of potential therapeutic use. For example, a compound known as Viscabelin has been obtained from one species of Alteromonas, and has been shown to exhibit antitumor activity (Japanese Patent Kokai Application Number Sho 63-27484).
With respect to the structure of thiomarinol, several antibiotic substances having similar structures are known, and these may be divided into three groups.
The first group comprises the pseudomonic acids, first isolated from Pseudomonas spp. These include pseudomonic acid A [produced by Pseudomonas fluorescens, disclosed in J. Chem. Soc. Perkin Trans. I, 294 (1977)], pseudomonic acid B [ibid, 318 (1977)], pseudomonic acid C [ibid, 2827 (1982)] and pseudomonic acid D [ibid, 2655 (1983)]. Pseudomonic acid A is marketed under the name "Bactroban" (Beecham, registered trade mark) in the form of a 2% dermatological ointment for antibacterial use.
Other pseudomonic acid derivatives have been obtained from marine bacteria [Am. Chem. Soc. Abstr. Pap., 200 (2), (1990)], but this reference does not disclose any antibacterial activity therefor.
The second group of substances sharing a similarity of structure with the compounds of the invention comprises that group which includes the antibiotics holomycin [Helv. Chim. Acta, 42, 563 (1959)], pyrrothine [J. Am. Chem. Soc., 77, 2861 (1955)], thiolutin [Angew. Chem., 66, 745 (1954)], aureothricin [J. Am. Chem. Soc., 74, 6304 (1952)], and others. These antibiotics are typically produced by actinomycetes, and are characterized by a sulfur-containing chromophore. Xenorhabdins I-V are substances related to holomycin, and have also been isolated from bacteria (disclosed in WO 84/01775).
Various studies on derivatives of these two groups have been performed, but we are not aware of any disclosure of a substance having the molecular structure of thiomarinol, or which is characterized by its properties.
The third group of compounds is disclosed in publications such as Japanese Application Kokai Numbers 52-102279, 54-12375, 54-90179, 54-103871 and 54-125672, which disclose pseudomonic acid derivatives having a similar structure to thiomarinol, but wherein the terminal carboxylic acid is replaced by an amide group. These compounds do not exert comparable antibacterial activity and do not exhibit a broad spectrum of antibacterial activity. In fact, these compounds demonstrate a tendency to possess weaker antibiotic activity than that of the original pseudomonic acid.